Helicobactor pylori (H. pylori) is a highly motile, S-shaped, microaerophilic bacterium that colonizes in the gut. H. pylori infection is widespread with seroprevalence in the developed world between 30-60% (Everhart, 2000). Infection with the bacterium is usually contracted during childhood and patients remain infected for life unless treated. H. pylori infection has been shown to result in the development of gastritis, peptic ulcer, and mucosa-associated lymphoid tissue (MALT) lymphoma and has been linked to gastric adenocarcinoma (Go, 2000). Eradication of H. pylori infection is currently achieved using combination therapy of antimicrobial and antisecretory agents (Malfertheiner, 2000). However, compliance to these therapies is compromised due to adverse side effects and cumbersome dosing regimens. In addition, increasing prevalence of H. pylori strains resistant to existing antimicrobial therapies threatens to limit the use of these treatments (Qureshi, 2000; Graham, 2000). Given these considerations, an ideal therapy for H. pylori infection would be a novel (no existing resistance mechanisms), monotherapy antimicrobial that is selective for H. pylori eradication. The selectivity attribute is expected to aid in minimizing side effects due to gut sterilization.
H. pylori, like all Gram positive and Gram negative bacteria, utilize a cell wall comprised of crosslinked peptidoglycan units to maintain shape and resist high osmotic pressure potentials. Bacterial cell wall biosynthesis is a validated target for antibimicrobial activity; cephalosphorins, penicillins and glycopeptides are antimicrobial agents, which block cell wall biosynthesis (Walsh, 2000). Cell wall biosynthesis requires the enzyme MurI, a glutamate racemase, and therefore this enzyme is essential for bacterial viability (Doublet, 1993).
The present invention describes compounds, which specifically inhibit H. pylori MurI, compositions of such compounds and methods of use. The compounds disclosed herein represent a valuable contribution to the development of selective therapies directed to diseases resulting from H. pylori infection.